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Activation of Melanocortin 4 Receptors Reduces the Inflammatory Response and Prevents Apoptosis Induced by Lipopolysaccharide and Interferon- in Astrocytes

Centro de Investigaciones en Reproducción (C.C., D.D., R.R., A.S., M.L.), School of Medicine, University of Buenos Aires, 1121ABG Buenos Aires, Argentina; Cedie (R.R.), Hospital de Niños R. Gutierrez, C1425 EFD Buenos Aires, Argentina; and Department of Neuroscience (H.B.S.), Uppsala University, BMC, 75124 Uppsala, Sweden

Address all correspondence and requests for reprints to: Mercedes Lasaga, Centro de Investigaciones en Reproducción, School of Medicine, University of Buenos Aires, Buenos Aires 1121ABG, Argentina. E-mail: mlasaga{at}fmed.uba.ar.

-MSH exerts an immunomodulatory action in the brain and may play a neuroprotective role acting through melanocortin 4 receptors (MC4Rs). In the present study, we show that MC4Rs are constitutively expressed in astrocytes as determined by immunocytochemistry, RT-PCR, and Western blot analysis. -MSH (5 µM) reduced the nitric oxide production and the expression of inducible nitric oxide synthase (iNOS) induced by bacterial lipopolysaccharide (LPS, 1 µg/ml) plus interferon- (IFN-, 50 ng/ml) in cultured astrocytes after 24 h. -MSH also attenuated the stimulatory effect of LPS/IFN- on prostaglandin E₂ release and cyclooxygenase-2 (COX-2) expression. Treatment with HS024, a selective MC4R antagonist, blocked the antiinflammatory effects of -MSH, suggesting a MC4R-mediated mechanism in the action of this melanocortin. In astrocytes, LPS/IFN- treatment reduced cell viability, increased the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells and activated caspase-3. -MSH prevented these apoptotic events, and this cytoprotective effect was abolished by HS024. LPS/IFN- decreased Bcl-2, whereas it increased Bax protein expression in astrocytes, thus increasing the Bax/Bcl-2 ratio. -MSH produced a shift in Bax/Bcl-2 ratio toward astrocyte survival because it increased Bcl-2 expression and also prevented the effect of LPS/IFN- on Bax and Bcl-2 expression. In summary, these findings suggest that -MSH, through MC4R activation, attenuates LPS/IFN--induced inflammation by decreasing iNOS and COX-2 expression and prevents LPS/IFN--induced apoptosis of astrocytes by modulating the expression of proteins of the Bcl-2 family.

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